Novel Role of Hepatic SEL1L-HRD1 ERAD in FGF21 Gene Transcription SUMMARY The liver regulates growth and systemic energy homeostasis through inter-organ communication via the secretion of growth factors, hormones and peptides. Fibroblast growth factor 21 (FGF21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism and insulin sensitivity. The Qi and Fang laboratories have been interested in the physiological roles of SEL1L and HRD1, respectively, focusing on different cell types. They are best known for their SEL1L-HRD1 protein complex in the endoplasmic reticulum (ER)-associated degradation (ERAD), a process responsible for the recruitment and retrotranslocation of ER proteins for cytosolic proteasomal degradation. In addition, studies have suggested that SEL1L may have HRD1- independent functions, and vice versa. In this study, the two laboratories are teaming up to define the role of SEL1L and HRD1 in hepatocytes. Remarkably, recent studies from our laboratories independently linked both SEL1L and HRD1 to FGF21 expression. Indeed, mice with hepatocyte-specific deletion of SEL1L or HRD1 exhibit strikingly similar phenotypes including growth retardation and female infertility with markedly elevated FGF21 levels in the liver and circulation. Mechanistically, we independently identified the ER-resident transcription factor CREBH as a possible molecular link between SEL1L/HRD1 on the ER membrane and FGF21 in the nucleus. Based on these strong preliminary data, we will test the hypothesis that hepatic SEL1L or HRD1 functions as an ERAD complex and together, controls systemic energy metabolism at least in part through the CREBH-FGF21 axis. To this end, we plan to independently and collaboratively test the following Aims: Aim 1 to determine whether hepatic SEL1L-HRD1 ERAD regulates systemic metabolism via modulation of FGF21 levels; and Aim 2 to demonstrate whether hepatic SEL1L-HRD1 ERAD regulates FGF21 gene transcription by targeting CREBH for proteasomal degradation. This study will not only establish the importance of SEL1L-HRD1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic ?ERAD-CREBH-FGF21? axis directly linking ER protein turnover to FGF21 gene transcription and systemic metabolic regulation. RELEVANCE TO HUMAN HEALTH: FGF21 is an important metabolic hepatokine that controls systemic energy metabolism and insulin sensitivity. This study will define the pathophysiological significance of SEL1L- HRD1 ERAD in hepatocytes and identify a novel hepatic ?ERAD-CREBH-FGF21? axis directly linking the function of ER protein degradation machinery to FGF21 gene transcription and systemic metabolic regulation.